Publications by authors named "Vanessa Soares Lara"

61 Publications

Fcγ receptors on aging neutrophils.

J Appl Oral Sci 2021 31;29:e20200770. Epub 2021 Mar 31.

Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciências Biológicas, Bauru, SP, Brasil.

Objective: Neutrophils are key effector cells of the innate immune system. They recognize antigens through membrane receptors, which are expressed during their maturation and activation. Neutrophils express FcγRII (CD32), FcγRIII (CD16), and FcγRI (CD64) after being activated by different factors such as cytokines and bacterial products. These receptors are involved with phagocytosis of IgG-opsonized microbes and enhance defense mechanisms. Based on that, our study seeks to compare the expression of FcγRII, FcγRIII, FcγRI, and CD11b on neutrophils from elderly and young subjects and their expression after in vitro activation with cytokines and LPS.

Methodology: Neutrophils were isolated from human peripheral blood and from mice bone marrow by density gradient. After isolation, FCγRs expression was immediately analyzed by flow cytometry or after in vitro stimulation.

Results: In freshly isolated cells, the percentage of FcγRIIIb+ and CD11b+ neutrophils were higher in samples from young individuals; FcγRIIIa expression was more prominent on aged neutrophils; FcγRIA expression was similar in all samples analyzed. Exposure to CXCL8 and LPS resulted in a higher percentage of FcγRIa+ neutrophils on elderly individuals' samples but lower when compared with neutrophils from young donors. We observed that LPS caused an increase in FcγRIIa expression on aging human neutrophils. In contrast, FcγRIIIb expression in response to CXCL8 and LPS stimulation was not altered in the four groups. CD11b expression was lower in neutrophils from elderly individuals even in response to LPS and CXCL8. In mice, we observed differences only regarding CD11b expression, which was increased on aged neutrophils. LPS exposure caused an increase in all FcγRs.

Conclusions: Our results suggest that, in humans, the overall pattern of FcγR expression and integrin CD11b are altered during aging and immunosenescence might contribute to age-related infection.
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http://dx.doi.org/10.1590/1678-7757-2020-0770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011831PMC
April 2021

Fibrin Biopolymer Incorporated with Antimicrobial Agents: A Proposal for Coating Denture Bases.

Materials (Basel) 2021 Mar 26;14(7). Epub 2021 Mar 26.

Department of Periodontics and Prosthodontics, Dental School of Bauru, FOB-USP-University of São Paulo, Al. Octávio Pinheiro Brisola, 9-75, Bauru 17012-901, Brazil.

The characteristics of the denture base surface, in combination with the oral environment, promote the colonization and development of biofilm, which is the main cause of denture stomatitis. This study evaluated the effectiveness of fibrin biopolymer with digluconate chlorhexidine or alcoholic extract to prevent biofilm. Conventional heat polymerized and pre-polymerized poly(methyl methacrylate) (PMMA) circular specimens (10 × 2 mm) were fabricated ( = 504) and randomly divided into groups: no treatment (control-CT), fibrin biopolymer coating (FB), fibrin biopolymer with (FBPg), or digluconate of chlorhexidine (FBCh) coating. The specimens were inoculated with SC5314 (1 × 10 cells/mL) and incubated for 24, 48, and 72 h. Crystal violet and colony-forming unit assays were used to quantify the total biofilm biomass and biofilm-living cells. A qualitative analysis was performed using confocal laser scanning microscopy. Data obtained are expressed as means and standard deviations and were statistically analyzed using a three-way analysis of variance (α = 0.05). The FBPg and FBCh groups inhibited the growth of biofilm in both PMMA materials analyzed, with FBCh performing better in all periods evaluated ( < 0.0001). The colony forming unit (CFU) assay showed that the FB group favored the biofilm growth at 24 h and 48 h ( < 0.0001), with no differences with CT group at 72 h ( = 0.790). All groups showed an enhancement in biofilm development up to 72 h ( < 0.0001), except the FBCh group ( = 0.100). No statistical differences were found between the PMMA base materials ( > 0.050), except in the FB group ( < 0.0001). Fibrin biopolymer, albeit a scaffold for the growth of when combined with chlorhexidine digluconate or , demonstrated excellent performance as a drug delivery system, preventing and controlling the formation of denture biofilm.
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http://dx.doi.org/10.3390/ma14071618DOI Listing
March 2021

Mast cells contribute to alveolar bone loss in Spontaneously Hypertensive Rats with periodontal disease regulating cytokines production.

PLoS One 2021 4;16(3):e0247372. Epub 2021 Mar 4.

Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil.

Mast cells (MCs) play a pivotal role in inflammatory responses and had been studied in inflammatory bone disorders, however, their role in alveolar bone loss induced by periodontal disease (PD) is not yet fully understood. We, therefore, aimed to evaluate the effects of MCs depletion in the PD-induced alveolar bone loss in Wistar (W) and Spontaneously Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk thread one day after the MCs depletion, by the pre-treatment with compound 48/80 for 4 days. After 15 days of PD induction, the hemi-mandibles were surgically collected for qRT-PCR, histological analyses, immunostaining, and ELISA. Systolic blood pressure (SBP) was verified by tail plethysmography to confirm the hypertensive status, and SHR presented SBP >150 mmHg, and previous MC depletion alone or associated with PD did not alter this parameter. SHRs showed a more severe alveolar bone loss compared to W, and MC depletion significantly inhibited this response in both strains, with a more significant response in SHRs. MCs were less abundant in 48/80+PD groups, thus validating the previous MCs depletion in our model. PD increased the number of MC in the gingival tissue of SHR. Cytokine production (TNF-α, IL-6, IL-1β, and CXCL3) was constitutively higher in SHR and increased further after PD, which was also significantly reduced in the MCs-depleted animals. PD led to an increased expression of Opn, Rankl, Rank, Vtn, Itga5, Itgb5, Trap, and Ctsk in the mandible of W and SHRs, which was reversed in MCs-depleted animals. These results suggest that MCs significantly contributes to the PD-induced alveolar bone resorption, especially in the SHR, which is associated with a more severe PD progression compared to Wistar, partly explained by these cells contribution to the inflammatory status and mediator production, stimulating osteoclast-related response markers, which were reduced after MC depletion in our experimental model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932174PMC
March 2021

Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease.

Front Pharmacol 2020 11;11:579926. Epub 2020 Nov 11.

Department of Basic Sciences, School of Dentistry, São Paulo State University (UNESP), Araçatuba, Brazil.

Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-α, IL-1β, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.
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http://dx.doi.org/10.3389/fphar.2020.579926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751694PMC
November 2020

Late complications after root coverage with two types of subepithelial connective tissue grafts, clinical and histopathological evaluation: A prospective cohort study.

J Clin Periodontol 2021 Mar 26;48(3):431-440. Epub 2021 Jan 26.

Discipline of Periodontics, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.

Aim: This prospective cohort study evaluated late complications (LC) on recipient sites comparing two types of connective tissue grafts (CTG).

Materials And Methods: Participants (n: 60) were treated with coronally advanced flap (CAF) plus CTG harvested by de-epithelialized technique (DE) (n:31) or two-parallel incision (PI) (n:29). Areas were evaluated to identify white discharge associated or not with gingival cul-de-sac. Patients were ordered in groups with (DE+and PI+) or without (DE- and PI-) LC. Biopsies for histopathological analysis in LC areas were proposed.

Results: Six cases exhibited LC, 5 in DE graft (DE+) and 1 in PI graft (PI+) group; 2 were diagnosed at 3 months postoperatively, 3 at 6 months and one at 12 months. The relative risk for LC was 1.7 times greater for DE graft (p: 0.01; CI: 1.10 to 2.72; RR>1). Differences were not observed for clinical outcomes after both types of CTGs (p > 0.05). Biopsies showed deep invagination of the epithelial lining suggesting cyst-like area/ cavity with keratin content and consolidated in fibrous connective tissue. After 24 months biopsied areas presented no recurrence of LC, in non-biopsied patients the clinical condition remained unchanged.

Conclusions: Considering the limitations of this study, LC on recipient sites demonstrated no statistical difference between two types of CTG.
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http://dx.doi.org/10.1111/jcpe.13413DOI Listing
March 2021

Antifungal activity of Punicalagin-nystatin combinations against Candida albicans.

Oral Dis 2020 Nov 29;26(8):1810-1819. Epub 2020 Jul 29.

Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil.

Objectives: Oral candidiasis is the most common opportunistic fungal infection of oral mucosa and results from an overgrowth of Candida, especially Candida albicans. The potential anti-C. albicans and cytotoxicity of punicalagin (PCG), isolated from Punica granatum, alone or with nystatin (NYS) were evaluated.

Methods: Activity of compounds alone or in combinations was determined against two C. albicans strains (ATCC 90028 and SC5314). Minimal inhibitory concentration (MIC)-50 and Minimum Fungicidal Concentration (MFC) were assessed by XTT assay and CFU counts, respectively. For combinations, determination of fractional inhibitory concentration index was performed. Ergosterol pathway was investigated as a possible PCG antifungal mechanism. Cytotoxicity assays were undertaken on human primary oral keratinocytes and gingival fibroblasts incubated with antifungal concentrations of PCG and/or NYS for 24 hr.

Results: Combination of NYS and PCG increased antifungal efficacy, compared with compounds tested alone. Combinations 4 (PCG-6.25 μg/ml; NYS-3.9 μg/ml) and 5 (PCG-12.5 μg/ml; NYS-1.95 μg/ml) were more effective since they reduced the MIC-50 of PCG (50 μg/ml) by 8 and 4 times, respectively, increased the candidal inhibition and nullified the PCG cytotoxicity for keratinocytes. PCG antifungal mechanism did not involve ergosterol biosynthesis pathway.

Conclusions: The favorable outcomes for combination of PCG and NYS encourage further testing this therapeutic strategy against C. albicans.
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http://dx.doi.org/10.1111/odi.13507DOI Listing
November 2020

What is the response profile of deciduous pulp fibroblasts stimulated with E. coli LPS and E. faecalis LTA?

BMC Immunol 2020 06 22;21(1):38. Epub 2020 Jun 22.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.

Background: Oral fibroblast immunological responses to bacterial stimuli are well known. However, there are few studies about pulp fibroblasts from deciduous teeth (HDPF) responses, which are important for the treatment of pulp infections in children. The aim of this study was to evaluate expression and production of inflammatory cytokines and chemokines by HDPF when challenged with bacterial antigens normally present in advanced caries lesions.

Methods: Triplicate HDPF from 4 children (n = 4; 2 boys and 2 girls) were cultured by explant technique and challenged or not with Escherichia coli lipopolysaccharide/1 μg/mL (EcLPS) or Enterococcus faecalis lipoteichoic acid/1 μg/mL (EfLTA) for 6 and 24 h. Most of published studies employed immortalized cells, i.e., without checking possible gender and genetic variables. mRNA expression and protein production were evaluated by RT-qPCR and ELISA MILLIPLEX®, respectively, for Interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, Chemokine C-C motif ligand 2/monocyte chemoattractant protein 1 (CCL2/MCP-1), Chemokine C-C motif ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP1-α), Chemokine C-C motif ligand 5/ regulated on activation, normal T cell expressed and secreted (CCL5/RANTES), C-X-C motif chemokine 12/ stromal cell-derived factor 1 (CXCL12/SDF-1), Tumor Necrosis Factor-alpha (TNF-α), Interferon-gamma (IFN γ), Vascular Endothelial Growth Factor (VEGF), Colony stimulating factor 1 (CSF-1) and Macrophage colony-stimulating factor (M-CSF).

Results: EcLPS increased IL-1α, IL-1β, IL-8, CCL2, CCL5, TNF-α and CSF-1 mRNA and protein levels while EfLTA was only able to positively regulate gene expression and protein production of IL-8.

Conclusion: The results of the present study confirmed our hypothesis, since pulp fibroblasts from deciduous teeth are capable of increasing gene expression and protein production after being stimulated with EcLPS and EfLTA.
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http://dx.doi.org/10.1186/s12865-020-00367-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310245PMC
June 2020

Should mast cells be considered therapeutic targets in multiple sclerosis?

Neural Regen Res 2020 Nov;15(11):1995-2007

Institute of Biosciences, Department of Microbiology and Immunology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.
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http://dx.doi.org/10.4103/1673-5374.282238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716037PMC
November 2020

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

Neurotherapeutics 2020 01;17(1):218-234

Department of Microbiology and Immunology, Institute of Biosciences, São Paulo State University (UNESP), Rua Dr. Plinio Pinto e Silva, S/N, Distrito de Rubião Júnior, Botucatu, São Paulo, 18618-691, Brazil.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.
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http://dx.doi.org/10.1007/s13311-019-00775-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007452PMC
January 2020

-Cell Interactions Activate Innate Immune Defense in Human Palate Epithelial Primary Cells via Nitric Oxide (NO) and β-Defensin 2 (hBD-2).

Cells 2019 07 12;8(7). Epub 2019 Jul 12.

Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry, University of São Paulo, 17012-901 Bauru, SP, Brazil.

The presence of in the biofilm underlying the dental prosthesis is related to denture stomatitis (DS), an inflammatory reaction of the oral mucosa. The oral epithelium, a component of the innate immune response, has the ability to react to fungal invasion. In this study, we evaluated the in vitro effect of viable on the apoptosis, nitric oxide (NO) production, and β-defensin 2 () expression and production of human palate epithelial cells (HPECs). We further determined whether or not these effects were correlated with fungal invasion of epithelial cells. Interaction between HPEC primary culture and was obtained through either direct or indirect cell-cell contact with a supernatant from a hyphal fungus. We found that the hyphae supernatants were sufficient to induce slight HPEC apoptosis, which occurred prior to the activation of the specific mechanisms of epithelial defense. The epithelial defense responses were found to occur via NO and antimicrobial peptide hBD-2 production only during direct contact between and HPECs and coincided with the fungus's intraepithelial invasion. However, although the hBD-2 levels remained constant in the HPEC supernatants over time, the NO release and gene expression were reduced at a later time (10 h), indicating that the epithelial defense capacity against the fungal invasion was not maintained in later phases. This aspect of the immune response was associated with increased epithelial invasion and apoptosis maintenance.
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http://dx.doi.org/10.3390/cells8070707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678605PMC
July 2019

Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease.

Front Pharmacol 2019 4;10:708. Epub 2019 Jul 4.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil.

The aim of this study was to characterize the role of local RAS (renin-angiotensin system) in the inflammatory response of normal (N) and diabetic (D) mice with periodontal disease (PD). Diabetes Mellitus (DM) was induced by peritoneal injection of streptozotocin in Balb/c mice. PD was induced by ligature around the first molar in both N and D, irrespective of whether they were treated with aliskiren (50 mg/kg, Alisk). Mandibles were harvested for histomorphometric analyses, and gingival tissue (GT) was collected to evaluate gene expression and extracellular matrix components (ECM). Immunohistochemical (IHC) analyses were used to localize RAS in GT. The production of C-reactive protein (CRP), IL-1β, CXCL2, and CCL8 was evaluated by enzyme-linked immunosorbent assay (ELISA). Renin was found to exacerbate the inflammation and periodontal bone loss at 14 days after PD, and Alisk inhibited this process in GT of N and D. PD increased CRP, CXCL2, CCL8, and IL-1β production in both animals. Alisk could inhibit CRP, CXCL2, and CCL8 primarily in D animals. However, only CCL8 was decreased in N animals after Alisk pretreatment. PD enhanced expression and production of AGT, ACE, AT1R, and AT2R in both N and D. AT1R expression was higher in D with PD, and AT2R expression was higher in N with PD. ACE2 and receptor Mas (MasR) expression and production was elevated in the control group of both animals. PD inhibited ACE2 in N but not in D. MasR expression was unaffected in both N and D with PD. Alisk reduced expression and production of all RAS components in GT of both animals, except for ACE2 in N. RAS staining was observed in all layers of epithelium, basal cell layer, and lamina propria and was higher in N with PD. Col1a1, Col1a2, Col3a1, and fibronectin (Fn1) were increased in both animals with PD. Alisk inhibited Col1a1 and Fn in both animals, Col1a2 was decreased only in D, while levels of Col3a1 remained unchanged in all animal groups. In conclusion, these data demonstrated the presence and functional role of local RAS in GT, exacerbating the inflammatory response, periodontal bone loss, and wound healing processes in both N and D animal groups. In addition, Alisk was able to significantly reduce gingival inflammation, excessive wound healing processes, and periodontal bone loss.
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http://dx.doi.org/10.3389/fphar.2019.00708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620569PMC
July 2019

Exuberant manifestation of neurofibromatosis type 1 affecting 3 generations: delayed diagnosis and the importance of the multidisciplinary approach.

Oral Surg Oral Med Oral Pathol Oral Radiol 2019 Sep 15;128(3):e108-e112. Epub 2019 Mar 15.

Department of Stomatology, School of Dentistry, Federal University of Amazonas, Manaus, AM, Brazil.

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder caused by mutations of chromosome 17. The NF1 clinical diagnosis is based on pre-established criteria, including the presence of cutaneous neurofibromas, café au lait spots, and iris (Lisch) nodules. Early detection and a multidisciplinary approach are essential for the prevention of complications, including problems of function, aesthetics, and self-esteem, as well as the occurrence of malignant transformation. This study reports a case of an exuberant NF1 manifestation diagnosed by a dental surgeon, whose investigation of a family led to the diagnosis of NF1, with different expressivities, in 3 generations.
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http://dx.doi.org/10.1016/j.oooo.2019.03.003DOI Listing
September 2019

In vitro treatment of Enterococcus faecalis with calcium hydroxide impairs phagocytosis by human macrophages.

Acta Odontol Scand 2019 Mar 8;77(2):158-163. Epub 2019 Jan 8.

a Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry , University of São Paulo , Bauru , Brazil.

Objective: Monocyte-derived macrophages (MDMs) ability to phagocytize and produce nitric oxide (NO) was tested against root-canal strains of Enterococcus faecalis submitted to alkaline stress. Root-canal strains were also compared with urine Enterococci.

Materials And Methods: Enterococcus faecalis were stressed with alkaline-BHI broth and incubated in vitro at a cell/bacteria ratio of 1:5. Phagocytosis was analyzed by fluorescence microscopy using acridine orange stain, and NO concentration was measured in supernatants.

Results And Conclusions: Alkaline-stress significantly impaired MDMs phagocytosis of E. faecalis strains analyzed, except in ATCC4083 isolated from a pulpless tooth, but NO production was unchanged. Comparison of different strains showed the urine isolate had higher NO levels than root canal strains. Alterations in the bacterial cell wall structures after alkaline-stress possibly made bacteria less recognizable and phagocytized by MDMs but did not affect their ability to activate NO production. Furthermore, root canal strains elicited different responses by immune cells compared with strains from urine. Clinically, impaired phagocytosis of E. faecalis could contribute to their persistence in root canal systems previously treated with calcium hydroxide.
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http://dx.doi.org/10.1080/00016357.2018.1533142DOI Listing
March 2019

ST2/IL-33 signaling promotes malignant development of experimental squamous cell carcinoma by decreasing NK cells cytotoxicity and modulating the intratumoral cell infiltrate.

Oncotarget 2018 Jul 20;9(56):30894-30904. Epub 2018 Jul 20.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil.

Squamous cell carcinoma (SCC) is the second most common form of skin cancer and the mechanism(s) involved in the progression of this tumor are unknown. Increases in the expression of IL-33/ST2 axis components have been demonstrated to contribute to neoplastic transformation in several tumor models and interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Based on these observations, we sought to determine the role of the IL-33/ST2 pathway during the development of SCC. Our findings show that ST2-deficiency led to a marked decrease in the severity of skin lesions, suggesting that ST2 signaling contributed to tumor development. An analysis of tumor lesions in wild-type and ST2KO mice revealed that a lack of ST2 was associated with specific and significant reductions in the numbers of CD4 T cells, CD8 T cells, dendritic cells, and macrophages. In addition, NK cells that were isolated from ST2KO mice exhibited higher cytotoxic activity than cells isolated from wild-type mice. Notably, ST2 deficiency resulted in lower IFN-γ, TNF-α, IL-10, and IL-17 production in tumor samples. Our findings indicate that the IL-33/ST2 pathway contributes to the development of SCC by affecting leukocyte migration to tumor microenvironment and impairing NK cytotoxic activity.
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http://dx.doi.org/10.18632/oncotarget.25768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089399PMC
July 2018

Subcellular localization and expression of E-cadherin and SNAIL are relevant since early stages of oral carcinogenesis.

Pathol Res Pract 2018 Aug 20;214(8):1185-1191. Epub 2018 Jun 20.

Department of Biological Sciences, Bauru School of Dentistry - University of Sao Paulo, Alameda Dr. Octávio Pinheiro Brisolla, 9-75, Bauru, SP, 17.012-901, Brazil. Electronic address:

The biological process of epithelial-to-mesenchymal transition (EMT) has been studied in oral squamous cell carcinoma (OSCC) metastasis, but it is rarely evaluated at several stages of oral carcinogenesis. This study aimed to analyze the presence of SNAIL and E-cadherin proteins, markers of EMT, in the development and progression of OSCC, evaluating excised specimens of potentially malignant lesions (oral leukoplakia with and without dysplasia-OL and OLD, respectively), tumor tissues (OSCC), metastatic lymph nodes (LN), and normal oral mucosa (NOM) by immunohistochemistry, considering subcellular localization. Additionally, SNAIL and E-cadherin transcripts were evaluated in vitro by qPCR, using SCC-9 cell line in comparison to human keratinocytes (HPEC). There was a significant increase in nuclear expression of SNAIL from NOM to OLD followed by a noticeable decrease in nuclear expression accompanied by increased cytoplasmic expression in OSCC (p<0.05). The E-cadherin cytoplasmic expression was remarkable and statistically significant higher in OSCC and LN, both compared to NOM (p< 0.0001), OL (p<0.01) and OLD (p< 0.0001 and p<0.001, respectively). In vitro, E-cadherin and SNAIL transcripts were lower in SCC-9 compared to HPEC cells, although only the decrease of E-cadherin was statistically significant (p<0.05). Regarding the association of E-cadherin and SNAIL expression with the clinical findings, the analysis revealed an association between the cytoplasmic expression of SNAIL and the invasion pattern (p=0.05) in OSCC. The increased nuclear SNAIL expression may be characteristic of OLD, and the presence of E-cadherin in cell cytoplasm a marker of transformation to malignancy of potentially malignant oral leukoplakias into OSCC.
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http://dx.doi.org/10.1016/j.prp.2018.06.004DOI Listing
August 2018

Antimicrobial activity of denture adhesive associated with Equisetum giganteum- and Punica granatum-enriched fractions against Candida albicans biofilms on acrylic resin surfaces.

Biofouling 2018 01 18;34(1):62-73. Epub 2017 Dec 18.

a Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry , University of São Paulo , Bauru , Brazil.

Candida biofilms adhere to the internal surface of removable dentures, which is an etiological factor in the pathogenesis of denture stomatitis (DS). Adhesive materials are used at the base of maxillary complete dentures to improve their retention and chewing qualities. This article reports the antimicrobial activity of the enriched fractions of Equisetum giganteum and Punica granatum incorporated into a denture adhesive against C. albicans biofilm. The biofilms were induced on the surface of heat-cured acrylic resin specimens that were previously treated with a mixture of adhesive/herb extracts. The antimicrobial activity was evaluated by CFU counts, XTT reduction, and SEM and CLSM analysis. Both herb extracts amplified the anti-biofilm action of the adhesive on the acrylic resin by up to 12 h. Therefore, when these extracts were combined with COREGA®, they played a collaborative and innovative role in biofilm control and can be considered alternatives for temporary use in the treatment and/or prevention of DS.
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http://dx.doi.org/10.1080/08927014.2017.1407408DOI Listing
January 2018

Oral cancer stem cells - properties and consequences.

J Appl Oral Sci 2017 Nov-Dec;25(6):708-715

Queen Mary University of London, Blizard Institute - Barts and The London School of Medicine and Dentistry, London, United Kingdom.

Research on cancer stem cells (CSCs) has greatly increased in the field of medicine and pathology; however, some conceptual misunderstandings are still present among the public as well as within the general scientific community that is not yet familiar with the subject. The very first problem is the misinterpretation of CSCs as a synonym of their normal counterparts, the well-known stem cells (SCs). Particularly in Dentistry, another common mistake is the misinterpretation of oral CSCs as normal tooth-derived SCs. The present review aims to clarify important concepts related to normal SCs and CSCs, as well as discuss the relevance of CSCs to the development, metastasis and therapy resistance of oral squamous cell carcinoma.
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http://dx.doi.org/10.1590/1678-7757-2016-0665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701542PMC
February 2018

CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development.

Mol Cancer Ther 2017 Dec 13;16(12):2871-2880. Epub 2017 Sep 13.

Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil.

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4CD25CCR5, CD4CD25CCR5 or CD8CCR5 conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4CD25CCR5 cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8 T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0341DOI Listing
December 2017

Phagocytosis and nitric oxide production by peritoneal adherent cells in response to Candida albicans in aging: a collaboration to elucidate the pathogenesis of denture stomatitis.

J Appl Oral Sci 2017 May-Jun;25(3):265-273

Universidade de São Paulo, Faculdade de Odontologia de Bauru, Departamento de Cirurgia, Estomatologia, Patologia e Radiologia. Bauru, SP, Brasil.

Objective: The aim of this study was to investigate the influence of aging on the internalization and the production of nitric oxide (NO) by peritoneal adherent cells (PAC), in response to Candida albicans (C. albicans).

Material And Methods: PAC obtained from young and aged mice were challenged with dead or viable C. albicans by using predetermined proportions (cells:yeast) for 30 and 120 minutes. Phagocytosis was analyzed by acridine orange dye, and NO production by the Griess reaction.

Results: C. albicans phagocytosis by PAC from aged mice was similar to that of young mice, although the cells from older mice cells present more internalized fungi compared with matched control. In addition, a tendency towards impaired NO production by peritoneal mononuclear phagocytes from aged mice was observed.

Conclusions: PAC from aged mice may capture and store many fungi, which in turn may mean that these cells are effectively unable to eliminate fungi, probably due to impaired NO production. Therefore, considering the important role of C. albicans overgrowth in the pathogenesis of DS and the aspects observed in this study, aging may favor the onset and severity of local candidosis such as DS and its systemic forms.
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http://dx.doi.org/10.1590/1678-7757-2016-0322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482249PMC
September 2017

Equisetum giganteum influences the ability of Candida albicans in forming biofilms over the denture acrylic resin surface.

Pharm Biol 2017 Dec;55(1):1698-1702

c Department of Prosthodontics , Bauru School of Dentistry, University of São Paulo (USP) , Bauru , SP , Brazil.

Context: Equisetum giganteum L. (Equisetaceae) is an endemic plant of Central and South America used in traditional medicine. Natural drugs have been frequently used in the treatment of a myriad of diseases, proving to be an alternative to synthetic chemicals, and have been intensively studied in the prevention of sicknesses, including oral diseases.

Objective: This study evaluated the in vitro antiadherent activity of E. giganteum extract against Candida albicans biofilms.

Materials And Methods: Crystal violet and colony-forming units assays were used to quantify the total biofilm biomass and biofilm living cells on a denture base acrylic resin pretreated with hydroethanolic extract of E. giganteum in different concentrations (50, 25, 16, 8, and 4 mg/mL), after 24 h of biofilm development.

Results: Equisetum giganteum affected biofilms by reduction of biomass and living cells per area of acrylic specimens. The results revealed reduction of 15-44% of the biofilm mass and reduction of numbers of colony-forming units (CFUs) present in biofilms (79%) compared to the untreated control (CTRL/PBS). At all concentrations, it demonstrated important antiadherent activity on Candida albicans biofilms, the main microbe in denture stomatitis.

Discussion And Conclusion: The present findings show that E. giganteum antimicrobial effects may qualify the extract as a promising natural alternative for topical treatment or prevention of denture stomatitis. The usage of drugs made of natural products shows advantages in relation to synthetic drugs on the market, such as lower cost, lower toxicity, and in relation to the occurrence of microbial resistance.
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http://dx.doi.org/10.1080/13880209.2017.1321024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130476PMC
December 2017

Ewing's Sarcoma Family Tumors in the Jaws: Case Report, Immunohistochemical Analysis and Literature Review.

In Vivo 2017 May-Jun;31(3):481-491

Department of Oral Pathology, Bauru School of Dentistry, University of Sao Paulo, Bauru, SP, Brazil.

Due to the low incidence of the Ewing's Sarcoma (ES) family tumors, the available epidemiology is likely to be unreliable, and at present, there are no standard diagnostic or clinical guidelines outlining their management. This report describes a case of peripheral primitive neuroectodermal tumor (ES/pPNET) which initially mimicked cystic lesions, and describes a comparison between ES and ES/pPNET in the jaws by the World Health Organization classification. This review addressed 63 cases published in the English literature between 1950 and 2016. The majority of cases were ES. Both ES and ES/pPNET mimicked other benign entities such as traumatic, cystic and inflammatory lesions. The patients who died of their disease had a history of metastatic tumors, and primary tumor located in the mandible and maxilla for ES and ES/pPNET, respectively. The differentiation of the ES family tumors from other small blue-cell tumors may be difficult and requires familiarity with histological and immunohistochemical features.
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http://dx.doi.org/10.21873/invivo.11087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461465PMC
February 2018

Giant oral lipoma: a rare entity.

An Bras Dermatol 2016 Sep-Oct;91(5 suppl 1):84-86

Bauru Dental School - University of São Paulo (USP) - Bauru (SP), Brazil.

Lipomas are very common benign slow-growing soft tissue neoplasms composed of mature adipose tissue mostly diagnosed in the fifth decade of life. These tumors rarely present in the oral cavity, representing less than approximately 5% of all benign mouth tumors. They are usually less than 2cm in size and etiology remains unclear. We report a young male patient presenting with a giant lipoma in the buccal mucosa. Histopathology revealed a large area of mature fat cells consistent with conventional lipoma and an area of the mucosal lining of the lesion suggestive of morsicatio buccarum. In the present article, we emphasize the clinicopathological features and differential diagnosis of the disease.
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http://dx.doi.org/10.1590/abd1806-4841.20165008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325003PMC
July 2017

Intraoral Device for Optimal Antifungal Delivery in a Rat Model.

Curr Drug Deliv 2017 ;14(5):658-667

Bauru School of Dentistry, University of São Paulo, Department of Prosthodontics, Bauru, São Paulo, Brazil.

Background: Antifungal agents incorporated into temporary denture resilient liners as drug carriers and delivery have been suggested as an alternative treatment for denture stomatitis. However, to test the in vivo biocompatibility of this protocol, standardization of an intraoral device for optimal drug delivery is required.

Objective: Standardized criteria were produced to adjust an acrylic intraoral device (IOD) for rats feasible for denture stomatitis treatment by sustained drug-delivery based on minimal inhibitory drug concentrations (MICs) of antifungals for Candida albicans biofilm.

Method: Adjustments methodological involved diet, impression technique, type of retention device to the palate and histopathological analysis. 115 Wistar rats were tested without IOD, with devices without relining or relined with temporary resilient material (Trusoft) modified or not by drugs at MICs (nystatin-0.032g/mL; chlorhexidine diacetate-0.064g/mL; ketoconazole-0.128g/mL). The animals were sacrificed after 7 or 14 days from the IOD installation.

Results: Paste diet enabled the best animal survival conditions. The IODs that most satisfactorily remained in position were those designed only to the posterior palatal mucosa and cement-retained in molars, being all obtained from impressions highly detained and individual. In both periods, Trusoft without/with drugs showed good performance. Only histological samples from hard/soft tissues were considered appropriate for region of interest-RI determination (n=12), which corresponded to the area restricted to the first molars between the palatal neurovascular bundles. Final samples of all groups allowed a standardized descriptive histopathological analysis in both periods.

Conclusion: The methodological standardization of this rat model resulted in IODs for optimal antifungal delivery for denture stomatitis treatment.
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http://dx.doi.org/10.2174/1567201813666161013122115DOI Listing
May 2018

Decreased production of proinflammatory cytokines by monocytes from individuals presenting Candida-associated denture stomatitis.

Cytokine 2016 Jan 14;77:145-51. Epub 2015 Nov 14.

Department of Stomatology, Bauru School of Dentistry, University of São Paulo: Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, 17012-901 Bauru, SP, Brazil. Electronic address:

Candida-associated denture stomatitis (DS) is the most frequent lesion among denture wearers, especially the elderly. DS is strongly associated with Candida albicans, as well as local and systemic factors, such as impaired immune response. Monocytes are important in the protective immune response against the fungus by the production of cytokines that recruit and activate leukocytes. There are functional changes in these cells with age, and individual alterations involving monocyte response may predispose the host to developing infections by Candida spp. In this study, our aim was to evaluate the production of TNF-α, IL-6, CXCL8, IL-1β, MCP-1 and IL-10 by monocytes from elderly denture wearers with/without DS and elderly or young non-denture wearers. We detected that monocytes from elderly denture wearers with Candida-related denture stomatitis produced lower levels of CXCL-8, IL-6 and MCP-1. This imbalance in cytokine levels was observed in spontaneous or LPS-stimulated production. Therefore, our data suggested that inherent aspects of the host, such as changes in cytokine production by monocytes, might be associated with the development and the persistence of DS irrespective of aging.
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http://dx.doi.org/10.1016/j.cyto.2015.10.017DOI Listing
January 2016

Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study.

J Appl Oral Sci 2015 Oct;23(5):459-66

Departamento de Estomatologia, Faculdade de Odontologia de Bauru, Universidade de São Paulo, Bauru, SP, Brazil.

Unlabelled: Although some morphological investigations on aged human sublingual glands (HSG) found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated.

Objective: The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death.

Material And Methods: 186 cadavers' glands were allocated to age groups: I (0-30 years); II (31-60), and III (61-90). Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM). Data were compared using Mann-Whitney U, Spearman's correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05).

Results: There was correlation between age and acinar autolysis (r=0.38; p=0.0001). However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis.

Conclusion: Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death.
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http://dx.doi.org/10.1590/1678-775720150139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621937PMC
October 2015

Mast cells phagocyte Candida albicans and produce nitric oxide by mechanisms involving TLR2 and Dectin-1.

Immunobiology 2016 Feb 7;221(2):220-7. Epub 2015 Sep 7.

Department of Stomatology, Bauru School of Dentistry, University of São Paulo: Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, 17012-901 Bauru, São Paulo, Brazil.

Candida albicans (C. albicans) is a fungus commonly found in the human mucosa, which may cause superficial and systemic infections, especially in immunosuppression. Until now, the main actors in the defense against this fungus are the epithelial cells, neutrophils, macrophages/monocytes and dendritic cells. However, mast cells are strategically located to play a first line of anti-Candida defense and it has appropriate mechanisms to do it. As with other cells, the recognition of C. albicans occurs meanly via TLR2 and Dectin-1. We assess the TLR2/Dectin-1 involvement in phagocytosis and production of nitric oxide (NO) and reactive oxygen species (ROS) by mast cells challenged with C. albicans. Bone marrow-derived mast cells (MC) from wild type (Wt) or knockout (TLR2-/-) mice C57BL/6 were subjected to in vitro Dectin-1 blockade. After challenged with FITC-labeled C. albicans or zymosan, phagocytosis was analyzed by microscopy. The intracellular production of NO and ROS was measured by DAF-FM diacetate and CellROX Deep/Red Reagent kits. The nitrite formation and hydrogen peroxide release were analyzed by Griess reaction and Amplex Red Hydrogen Peroxide/Peroxidase Assay Kit. Wt/MC phagocytose C. albicans with production of intracellular NO, but not ROS. Moreover, increased levels of nitrite were also observed. The absence and/or blockade of TLR2/Dectin-1 caused significant decreased in C. albicans phagocytosis and NO production. Our results showed that mast cells are able to phagocytose and produce NO against C. albicans via TLR2/Dectin-1. Therefore, mast cells could be important during the course of Candida infection and as a therapeutic target.
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http://dx.doi.org/10.1016/j.imbio.2015.09.004DOI Listing
February 2016

Expression of Secreted Aspartyl Proteinases in an Experimental Model of Candida albicans-Associated Denture Stomatitis.

J Prosthodont 2016 Feb 7;25(2):127-34. Epub 2015 Apr 7.

Department of Stomatology (Oral Pathology), Bauru School of Dentistry, University of São Paulo, Bauru, Brazil.

Purpose: Candida albicans is known to produce secreted aspartyl proteinases (SAPs) to aid adhesion, invasion, and host tissue destruction. SAPs may contribute to denture stomatitis (DS) pathogenesis. The aim of this study was to develop an in vivo experimental model for Candida-associated DS that allows the analysis of SAP2, SAP5, and SAP9 expression by C. albicans from biofilm induced on the denture surface.

Materials And Methods: Thirty-five male Wistar rats were divided into three groups: control, denture, and denture/Candida group. The last two groups remained with dentures for 2, 4, and 6 days, with or without induced biofilm. SAP expression was concomitant with leukocyte counts as well as clinical and histological changes shown by animal palate.

Results: The signs observed at 4 days in the denture/Candida group were clinically closer to the Candida-associated DS, showing a significant increase of neutrophils and decrease of lymphocytes in peripheral blood, presence of inflammation signs on the palate similar to DS Newton type I, and fungal invasion in the epithelial layer. Accordingly, the denture/Candida group at 4 days presented the highest relative expression of all SAPs studied.

Conclusion: The results showed a coincidence between SAP expression and clinical, microscopic, and blood data. Finally, the molecular findings were consistent with the virulence capacities of C. albicans from biofilm formed on the denture resin, which possibly allowed epithelial invasion by the fungus.
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http://dx.doi.org/10.1111/jopr.12285DOI Listing
February 2016

Aging does not affect the ability of human monocyte-derived dendritic cells to phagocytose Candida albicans.

Aging Clin Exp Res 2015 Dec 18;27(6):785-9. Epub 2015 Mar 18.

Department of Stomatology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, Bauru, SP, 17012-901, Brazil.

Background: Dendritic cells (DCs) are the most potent antigen-presenting cells, playing a key role in induction of both innate and adaptive immunity. Immunosenescence refers to age-associated changes in the immune system, which may be associated with susceptibility to infections and their clinical complications. The precise effects of aging on DCs in immunity to infections are not well understood. Among the common pathogenic microorganisms, the fungus Candida albicans is an important pathogen for the development of invasive infections, especially in immunocompromised individuals, as well as during aging.

Aims: To make a comparative in vitro evaluation of the immunomodulatory function of DCs challenged with C. albicans, by phagocytosis of the fungal cells, and determine the involvement of TLR2 and TLR4 receptors. For this purpose, DCs were generated with the use of peripheral blood monocytes from healthy young and aged subjects.

Results: The phagocytosis of C. albicans is developed by DCs in TLR2- and TLR4-dependent way. This mechanism is not affected by aging.

Conclusion: Given the important role of the DCs in responses against the fungus, it is evident that if changes in phagocytosis occurred with aging, impairment in the elderly could develop. However, the evidence that phagocytosis of this fungus by DCs is not impaired with aging, brings us to the question of which are the mechanisms truly associated with the prevalence of certain diseases in the elderly.
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http://dx.doi.org/10.1007/s40520-015-0344-1DOI Listing
December 2015